Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein on analyses of existing family data from the Beaver Dam Eye Study. In this study, a private census of the town and township of Beaver Dam, Wisconsin was performed and all individuals between the ages of 43-84 were asked to enroll, were given extensive eye examinations and asked to fill out a questionnaire that measures environmental risk factor exposures. Of the 5925 eligible people, 4926 (83.1%) participated. Within this dataset, there are 1,247 people from 564 sibships with at least 2 members in each sibship having complete age, sex and examination results. These families represent an outstanding data resource for examining major genetic components to various eye diseases. We are currently analyzing genome-wide scan data on the entire Beaver Dam cohort of families for glaucoma, IOP, refractive error, myopia, hyperopia, and various forms of cataracts. We plan fine-mapping studies in several regions that have shown significant evidence of linkage. Three papers were published in this fiscal year and several others are in preparation. A study of the genetics of myopia in collaboration with Dr. Dwight Stambolian is ongoing. Dr. Stambolian is continuing to collect pedigrees with myopia from 5 populations. In this fiscal year, a paper was published presenting results of our genome-wide linkage analysis of the Amish families. Analyses of refractive error in the Ashkenazi Jewish and Amish families have revealed evidence of a QTL on chromosome 1 and two papers are in preparation. Additional families have been genotyped for a genome wide scan and will be analyzed in the next fiscal year. In addition, a dense map of SNP markers has been genotyped in the Ashkenazi families to follow up the chromosome 22 linkage, and significant association in the region of one candidate locus has been found. This gene is currently being sequenced in our linked families and in normal individuals, in order to detect mutations or functional polymorphisms that may increase risk of myopia. Dr. Bailey-Wilson is a member of a collaborative study of Attention Deficit Hyperactivity Disorder, collaborating with Drs. Max Muenke and Kate Berg of NHGRI and Dr. Mauricio Arcos-Burgos of NHGRI and University of Antioquia, Columbia. Dr. Bailey-Wilson's role is to help with study design and to serve as advising statistical geneticist on the project. Genome-wide scan genotyping and inkage analysis has been completed on the first set of families followed by finemapping. A paper has been published detailing our evidence of linkage of ADHD to 4q132, 5q333, 11q22, and 17p11. Another paper was published examining evidence for other comorbid psychiatric disorders in these families. Studies are ongoing to followup these results. Dr. Bailey-Wilson is collaborating with Drs. Steven Brant and Theodore Bayliss of Johns Hopkins University School of Medicine, with the International IBD Consortium and with the Middle Atlantic African American Inflammatory Bowel Disease Study. Currently, the IBD Consortium has finished genotyping the families for additional candidate genes and is analyzing these data and have performed a meta-analysis of published genome wide screens. Dr. Bailey-Wilson is a member of the Analysis committee for this consortium and will continue to interact with Drs. Brant, Bayliss and the IBD Consortium on future analyses of the genetics of IBD. Dr. Bailey-Wilson also is collaborating with Drs. Brant and Bayliss and Dr. Carolien Panhuysen of Boston University on analyses of Dr. Brant's, Cho?s and Duerr?s IBD data. Linkage and association studies of genome-wide scan and fine mapping data are ongoing. Several papers are in preparation. Finally, Dr. Bailey-Wilson and her graduate student, Betty Doan, have worked with Dr. Brant to type markers in additional candidate regions and to analyze these data for linkage and association analysis, and to also reanalyze Dr. Brant?s data including environmental covariate data. This work is ongoing. Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic, Dr. Diego Wyszynski of Boston University and Dr. Terri Beaty of Johns Hopkins School of Public Health on a linkage study of oral clefts. In this fiscal year, data collection is ongoing in the Syrian Arab Republic, of clinical information and blood samples for genotyping from highly inbred families with many members affected with cleft lip and palate. New Syrian families have been genotyped for genome-wide scan markers and analyses of these data are ongoing. Results of a collaborative segregation analysis with Dr. Rasika Mathias of NHGRI and Dr. Terri Beaty of Johns Hopkins School of Public Health were published this year, exploring the complex inheritance pattern of serum IgE in an isolated U.S. population. Another set of projects led by Dr. Priya Duggal, a senior postdoctoral trainee in the Section, encompass the human genetic predisposition to infectious diseases including Visceral leishmaniasis, Amebiasis and HIV/AIDS. Visceral leishmaniasis is a potentially fatal disease caused by the protozoan Leishmania chagasi that is carried by the sandfly. Recently, we collected complete clinical and environmental factor data for 1106 members of 216 families living in endemic neighborhoods in Brazil. In this fiscal year Dr. Duggal has conducted a genome wide linkage analysis for visceral leishmania and the related immune response DTH on genotype data provided by CIDR. In our case-control studies of mucosal and cutaneous leishmaniasis we have identified a functional SNP in IL-6 that is associated with individuals developing mucosal versus cutaneous leishmaniasis. Additional SNPs in IL-6 are currently being genotyped, and we have also now collected extended pedigrees from the cases to determine if there is a family based association. Amebiasis is a large contributor to diarrheal disease in the developing world. Amebiasis is caused by infection of the intestine by the parasite Entamoeba histolytica. Infection with E. histolytica is heterogeneous and it is very likely that genetic predispositions/susceptibility influence acquisition and progression of this parasite in humans. Dr. Duggal and her collaborators have recently shown that the IgA immune response to the carbohyrdrate region domain of E. histolytica provides protection from subsequent infections with E. histolytica, although it is not long lived. This finding may be critical to the development of a vaccine for amebiasis. (Paper submitted and under review) Dr. Duggal also aims to understand genetic host susceptibility to HIV/AIDS, using a cohort of 3000 injection drug users in Baltimore, Maryland that participate in the AIDS Link to Intravenous Experience (ALIVE). Population based genetic studies including this cohort have identified numerous candidate genes that affect HIV/AIDS disease progression. A paper presenting some of these results was published this fiscal year. Part of the APOBEC compex is the CUL5 factor. In our study of African American injection drug users, we have recently identified a cluster of haplotypes driven by 3 SNPs that influences progression to AIDS, and also has a strong influence on CD4 cell counts. There is also a strong additive interaction with our previous finding in APOBEC3G (a paper is in preparation).